rs796053157

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001040142.2(SCN2A):c.4886G>A(p.Arg1629His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.98

Variant links:

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SCN2A links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001040142.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 2-165388692-G-A is Pathogenic according to our data. Variant chr2-165388692-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.4886G>A	p.Arg1629His	missense_variant	Exon 27 of 27	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.4886G>A	p.Arg1629His	missense_variant	Exon 27 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.4886G>A	p.Arg1629His	missense_variant	Exon 27 of 27	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.4886G>A	p.Arg1629His	missense_variant	Exon 27 of 27	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.4886G>A	p.Arg1629His	missense_variant	Exon 27 of 27	1		ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 11

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4886G>A (p.Arg1629His) missense variant in SCN2A gene has been reported in an individual with neonatal seizures and severe intellectual disability (Wolff et al., 2017). The variant has also been reported in a child with neonatal onset of multifocal seizures and developmental delay (Sandu et al., 2017). The p.Arg1629His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 1629 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the fourth homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic/Uncertain Significance. The amino acid change p.Arg1629His in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN2A-related disorders (Nakamura et al., 2013; Nashabat et al., 2019). For these reasons, this variant has been classified as Likely Pathogenic. -

Oct 05, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2019

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Aug 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4886G>A (p.R1629H) alteration is located in exon 27 (coding exon 26) of the SCN2A gene. This alteration results from a G to A substitution at nucleotide position 4886, causing the arginine (R) at amino acid position 1629 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in multiple unrelated patients with epilepsy (Hamdan, 2017; Wolff, 2017; Kong, 2019). In addition, two other alterations affecting the same amino acid, p.R1629P and p.R1629L, were reported in patients with epilepsy (Nakamura, 2013; Symonds, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11

Pathogenic:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1629 of the SCN2A protein (p.Arg1629His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 28379373, 29100083, 30619928, 31054490). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207019). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Feb 16, 2022

Neurology Department, Shenzhen Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jan 15, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28379373, 29100083, 30619928, 32090326, 32411386, 32712949, 33951346, 31785789, 34247411, 34894057, 35431799, 33057194, 37429183, 35982159, 31054490) -

Epilepsy of infancy with migrating focal seizures

Pathogenic:1

Department of Neurology, Children’s Hospital of Chongqing Medical University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Seizures, benign familial infantile, 3

Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complex neurodevelopmental disorder

Pathogenic:1

Jul 10, 2019

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-07-10 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight and, in one family in multiple siblings. Additional phenotypic information for other sibling(s) might be available from Simons Searchlight. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;T;.;D;D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D;.;.;.;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

H;H;.;H;H;H;H

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.3

D;.;.;.;.;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.;.;.;.;D;D

Sift4G

Uncertain

0.0090

D;.;.;D;.;D;D

Polyphen

0.10

B;D;.;D;B;B;D

Vest4

0.87

MutPred

0.85

Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);.;Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);

MVP

1.0

ClinPred

1.0

GERP RS

5.5

Varity_R

0.84

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over